POS1287 INFLUENCES ON FIBROMYALGIA AND AUTOANTIBODIES DIRECTED TO NEURO- AND VASOREGULATORY MOLECULES NEED TO BE CONSIDERED IN BIOMARKER RESEARCH
Authors: F. Lübber, J. Strobach, H. Heidecke, T. Lange, G. Riemekasten
Journal: Annals of the Rheumatic Diseases (2022)

Background Fibromyalgia syndrome (FMS) is often present in autoimmune diseases but can also occur in its primary form. Biomarkers for FMS are currently missing. Systemic chronic inflammation, dysautonomia and metabolic dysfunction have been suggested to contribute to the disease. Recent studies indicate that FMS involves autoantibodies (abs), which bind to neurons, macrophages and endothelial cells. Objectives In the present study, we aimed to delineate changes in natural abs directed to neuro- and vasoregulatory molecules and potentially confounding factors, which could influence these abs and disease state. Methods Sera from 91 patients with primary FMS (pFMS), 24 patients with secondary FMS (sFMS) and 31 healthy controls (HC) were analysed for the presence of 27 different natural abs directed to e.g., cholinergic, opioid, cannabinoid, endothelin or complement receptors or angiotensin system molecules by individual ELISAs (CellTrend GmbH, Luckenwalde, Germany). All participants were characterized by several questionnaires to obtain demographic data and measures of disease state (using the Widespread Pain Index (WPI) and Symptom Severity Score (SSS)). Linear regression on log-transformed ab levels adjusted for potential confounders was used to compare ab levels between groups. Random forest analysis was applied to differentiate between pFMS and HC by measuring the Area Under the Curve Receiver operating characteristics (AUC-ROC). Results Compared to HC, patients with pFMS showed increased levels of abs directed to ACE II, the angiotensin receptor type-2 (AT2R), the cannabinoid receptor type 1 and 2 (Can1-R, Can2-R), the endothelin receptor type-B (ETBR), the opioid receptor κ (Op-k-R) and lower levels against the complement receptor 5a (C5a-R) and the muscarinergic acetylcholine receptor type 3 (M3)(Figure 1). After adjustment for age (linear and squared) and sex, differences in the ab levels remain significant for abs against ACE II, AT2R, ETBR and the Op-k-R. However, none of which remained significant after further adjustment for Body Mass Index (BMI). Random forest analysis of unadjusted ab levels revealed an AUC-ROC of 0.94 for pFMS compared to HC with an average accuracy of 0.85 and a kappa of 0.55. Again, after adjusting the ab levels for age, sex and the BMI, AUC-ROC to discriminate HC from pFMS patients decreased to 0.73 (accuracy = 0.79, kappa = 0.33). Figure 1. Boxplots of logarithmized abs levels between groups. *: p &lt; .05 in unadjusted analysis and after adjusting for age and sex, ~: p &lt; .05 only significant after adjusting for age and sex, +: p &lt; .05 only in unadjusted analysis (all FDR-corrected within group comparisons across abs). Unadjusted Adjusted for age, sex and BMI Conclusion Abs might be potential biomarkers for pFMS. However, these results highlight the important role of correct covariate adjustment for research on biomarkers supposed to classify FMS or other diseases. In FMS, increase in BMI might be a cause or a consequence of FMS and it is also unknown how BMI and abs influence each other. Thus, BMI might or might not be a confounder so that adjusting for BMI might be correct or incorrect. However, these abs could provide a link to understand how acquired conditions interact with the immune system. References [1]Goebel A et al. Passive transfer of fibromyalgia symptoms from patients to mice. J Clin Invest. 2021 Jul 1;131(13):e144201. [2]Cabral-Marques O et al. GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis. Nat Commun. 2018 Dec 6;9(1):5224. Figure 2. AUC ROC as detected by random forest analysis in pFMS patients versus HC for unadjusted ab levels as well as for ab levels adjusted for age, sex, and BMI. Disclosure of Interests None declared